tbuckley/cabot-search huggingface dataset:
Systematic review and meta-analysis evaluating the impact of antibiotic use on the clinical outcomes of patients with cancer treated with immune checkpoint inhibitors.
Authors: Gerard Zalcman, Athéna Crespin, Julie Cervesi, Clément Le Bescop, Renaud Buffet, Jean de Gunzburg, Fabien Vitry, Pierre-Alain Bandinelli
Journal: Journal of Clinical Oncology (2022)

2585 Background: In recent years, the gut microbiome has increasingly emerged as influencing the response to immune checkpoint inhibitors (ICIs) and antibiotic (ABX) exposure has repeatedly been shown to impair clinical outcomes of patients suffering from different cancer types and treated with ICIs. We published in 2020 a meta-analysis confirming that ABX use hampered survival of non-small cell lung cancer (NSCLC) patients treated with ICIs. The present study aims to determine whether ABX use also reduces survival of patients receiving ICIs for other cancers. Methods: PubMed and major oncology conferences’ proceedings were systematically searched to identify studies assessing the impact of ABX on the clinical outcomes of cancer patients treated with ICIs. Studies were included when reporting data on Overall Survival (OS), Progression-Free Survival (PFS), Overall Response Rate (ORR) and Progressive Disease Rate (PD), according to ABX exposure. Pooled Hazard Ratios (HRs) for OS and PFS and Odds Ratios (ORs) for ORR and PD were calculated, as well as HRs for OS and PFS according to different cancer types and different ABX exposure time windows (TWs). Results: Overall, 94 independent cohorts were included, representing 26,174 patients suffering from various types of cancer. The pooled HRs for PFS (61 cohorts, 13,224 patients) and OS (88 cohorts, 25,480 patients) were 1.47 [95% Confidence Interval (CI) 1.31-1.66] and 1.66 [95% CI 1.50-1.83], respectively, confirming a significant harmful impact of ABX on patient’ survival, observed across all cancer types (Table). The analyses of OS and PFS based on ABX exposure TWs suggested a stronger deleterious effect of ABX when taken around ICI treatment initiation. The response to treatment among ABX users was also impaired: the pooled ORs for ORR (30 cohorts, 4,590 patients) and PD (33 cohorts, 4,972 patients) were 0.55 [95% CI 0.39-0.77] and 1.97 [95% CI 1.48-2.64], respectively. Conclusions: ABX were shown to impair the clinical outcomes of cancer patients treated with ICIs, regardless of cancer type. [Table: see text]
Navtemadlin (KRT-232) activity after failure of anti-PD-1/L1 therapy in patients (pts) with <i>TP53<sup>WT</sup></i> Merkel cell carcinoma (MCC).
Authors: Michael K.K. Wong, Melissa Amber Burgess, Sunandana Chandra, Dirk Schadendorf, Ann W. Silk, Anthony J. Olszanski, Jean-Jacques Grob, Sekwon Jang, Jaspreet Singh Grewal, Karl D. Lewis, Leslie Anne Fecher, Guilherme Rabinowits, Celeste Lebbe, Annalise Shen, Tiffanie Chan, Jesse S. McGreivy, Wayne P. Rothbaum, Glenn J. Hanna, Ciara Marie Kelly
Journal: Journal of Clinical Oncology (2022)

9506 Background: MCC is a rare, aggressive, neuroendocrine skin cancer with a high risk of recurrence and metastases. A median survival of about 4 mo for pts with metastatic MCC who failed anti-PD-1/L1 therapy highlights an urgent need for novel therapies. In TP53 WT MCC, oncoproteins from the Merkel cell polyomavirus (MCPyV) inhibit p53 tumor suppressor functions by activating murine double minute 2 (MDM2). Navtemadlin is a potent, selective, orally available MDM2 inhibitor that overcomes MDM2 dysregulation by restoring p53 activity and inducing apoptosis of TP53 WT tumors. Methods: The dose-finding, phase 1b/2 KRT-232-103 study (NCT03787602) evaluated navtemadlin in adult TP53 WT MCC pts who failed anti-PD-1/L1 therapy. Pts were randomly assigned to oral navtemadlin once daily in 21- or 28-day cycles: 240 mg 7 days (D) on/14D off or 5D on/23D off, 180 mg 5D on/23 D off or 7D on/21D off, or 120 mg 7D on/14D off, until disease progression or unacceptable toxicity. The primary endpoint was Recommended Phase 2 Dose (RP2D); objective response rate (ORR) was assessed per RECIST v1.1. Results: As of Nov 30, 2021, 31 pts were enrolled with median age 66 y (range, 25-82); 52% had visceral disease and 71% had received ≥2 lines of prior therapy. Baseline tumor profiling of available samples showed low tumor mutation burden, MCPyV-positivity, and nonamplified MDM2 gene in 100%, 92%, and 100% of pts, respectively. Treatment-emergent adverse events (TEAEs) were observed in 100% (68% grade 3/4) of pts. The most common Grade 3/4 TEAEs were hematologic: 32% anemia, 32% lymphopenia, and 19% thrombocytopenia. Navtemadlin doses ≤180 mg were well tolerated with fewer dose reductions and longer treatment durations; subsequently the 240 mg arms were closed to further enrollment. Evaluable pts receiving 180 mg 5D on/23D off showed a 25% confirmed ORR, a 38% unconfirmed + confirmed ORR, and a 63% disease control rate (Table); median duration of response was not reached (range, 6-16.2+ mo) and median time to treatment response was 4.1 mo (range, 1.2-7). Notably, one responder, following a prolonged partial response, achieved complete metabolic remission by PET/CT after 2 y on treatment. The 120 mg arm was closed due to a low response rate. The 180 mg dose has been selected for further evaluation. Conclusions: Navtemadlin is the first targeted agent to show promising single-agent activity in heavily pretreated MCC pts who failed anti-PD-1/L1 therapy. This study demonstrates that upregulation of the p53 pathway is a viable therapeutic strategy in MCC. Clinical trial information: NCT03787602. [Table: see text]
Incidental pulmonary nodules, lung cancer screening, and lung cancer in the Medicare population.
Authors: Raymond U. Osarogiagbon, Eric A Miller, Nicholas Faris, Paul F Pinsky
Journal: Journal of Clinical Oncology (2022)

6536 Background: Low-dose CT lung cancer screening (LDCT) saves lives, but only 5%-10% of eligible persons in the US have participated. Management of indeterminate pulmonary nodules (IPNs) identified on CT scans may also reduce lung cancer mortality. We assessed the frequency of IPNs, estimated cumulative lung cancer rates following IPNs, and compared characteristics of lung cancers diagnosed following IPNs versus LDCT screens. Methods: We defined 2 cohorts in the SEER-Medicare database: persons with 12+ months of Medicare Part A&amp;B coverage during 2014-2019 comprised the 5% sample cohort; persons in SEER-Medicare diagnosed with lung cancer during 2015-2017 with Part A&amp;B coverage for the prior 18-month period comprised the lung cancer cohort. We defined IPNs as chest CTs with ICD-10 codes of R91.1 (solitary pulmonary nodule) or R91.8 (other nonspecific abnormal finding of lung field) on the same date as the CT; we used corresponding ICD-9 codes through September 2015. We classified lung cancer cohort cases by whether they had an LDCT (LDCT group), an IPN without an LDCT screen (IPN-only), or neither (Referent) within 18 months before diagnosis. We compared cancer stage and survival between these groups. Results: Of 627,547 subjects in the 5% sample cohort, 58.6% were women; 85.6% were non-Hispanic White (NH-Whites) and 7.7% non-Hispanic Black (NH-Blacks). Over median 5.0 years follow-up, 26.3% had chest CTs and 12.0% had IPNs. The IPN rate was similar by sex but significantly higher in NH-Whites (12.7%) than NH-Blacks (9.7%). The cumulative lung cancer rate following initial IPNs was 2.27% at two years. Of the 44,194 lung cancer cohort cases (85.8% NH-White, 8.2% NH-Black), 26.9%, 2.9% and 70.2% were in the IPN-only, LDCT, and Referent groups, respectively. NH-Whites comprised a higher proportion of LDCT than of IPN-only cases (90.1% vs. 88.4%), while for NH-Blacks, the reverse was true (5.4% vs. 6.5%). The ratio of LDCT:IPN lung cancer cases was 1:9. Among IPN-only and LDCT group cases, 52.0% and 50.3%, respectively, were localized stage, compared to 21.5% for the Referent group. Among all localized cases, 45.4% and 4.9% were in the IPN-only and LDCT groups, respectively. Comparing 3-year survival between IPN vs LDCT vs Referent groups, respectively: aggregate overall survival rates were 53.5% v 59.2% v 29.2%; aggregate lung cancer-specific survival, 71.1% v 75.3% v 46.6%; overall survival for localized cases, 73.2% v 80.7% v 62.9%; lung cancer-specific survival rates for localized cases, 88.2%, 91.8% and 81.4%. Conclusions: Subjects with IPNs had similar stage distribution and survival as LDCT-screened subjects. Almost half of localized cases had prior IPNs, compared to a &lt; 5% of LDCT-screened cases. IPN programs, by circumventing implementation barriers to LDCT, may expand access to early lung cancer detection, including to African American patients and in places where LDCT coverage is not available.
Factors affecting outcomes in gallbladder cancer: A single institution retrospective analysis.
Authors: Haris Hatic, Peng Li, Ravi Kumar Paluri
Journal: Journal of Clinical Oncology (2022)

e16109 Background: Gallbladder cancer is one of the highest fatal malignancy. We conducted a retrospective analysis to study the outcomes of gallbladder malignancy in an academic care setting. Methods: Data was collected retrospectively on patients treated at University of Alabama at Birmingham between January 2005 and June 2015 from the electronic medical record using a standardized data collection tool (Redcap). We evaluated for predictors of overall survival (OS) and progression-free survival (PFS). Results: Of the 93 patients in this study, 66% were female. Adjuvant chemotherapy (CT) was given to 11% and adjuvant chemoradiation (CRT) to 14%. On multivariate analysis, albumin &gt; 3.5, uninvolved margins, absence of lymphovascular/peri-neural invasion were independent predictors of OS and PFS (Table). The overall median survival was 24.3 months with a 5-year median OS at 23.7%. Surgery with CRT for the full cohort had a median OS of 54.4 vs 15.6 (p = 0.0048) months compared to surgery CT alone. The OS in stage 3-4 patients with surgery alone vs surgery &amp; CT was 5.5 versus 28.7 months respectively (p = 0.0052). The PFS for the same group was 17.5 vs 4.6 months (p = 0.0052). Conclusions: The dismal survival rates of gallbladder cancer made. adjuvant therapy (CT or CRT) critically important. Concurrent chemoradiation needs to be evaluated in randomized clinical trials for potential improvement in clinical outcomes compared to currently approved standard of care, adjuvant CT alone. [Table: see text]
Integrative analysis of plasma cell-free DNA fragmentation and methylation patterns for colorectal cancer detection.
Authors: Seungho Shin, Shin-Sang Jo, Clémentine Charton, Stephanie Kim, Hyeyeun Lim, Sol-yi Kim, Jongsuk Chung, Hye Kyung Hong, Yong Beom Cho, Jinho Kim, Donghyun Park
Journal: Journal of Clinical Oncology (2022)

e15022 Background: Recently, the analysis of epigenetic traits of cfDNA has been ben proven to be effective in early non-invasive cancer detection. Although integrating the DNA fragmentation and methylation information is expected to improve cancer detection performances, there are technical hurdles for effective integration of these data for detecting cancer non-invasively. In this study, we generated and analyzed targeted methylation sequencing data to develop a cancer detection method that uses both methylation and DNA fragment size patterns, optimized parameters for the model and evaluated the accuracy of the model in colon adenocarcinoma patients. Methods: Plasma cfDNA was collected from a total of 215 donors (111 COAD patients and 104 healthy adults) and targeted methylation sequencing data was generated using a customized panel covering 196k CpG sites containing robustly evaluated cancer specific markers. A total of 60 COAD and healthy samples, respectively, were used to train the model using elastic net and logistic regression. The remaining COAD 51 and healthy 44 samples were used as the test dataset in evaluating the model. Results: The integrative method achieved a high performance (94.12% sensitivity and 97.93% specificity) in classifying COAD patients and healthy individuals. Interestingly, when we decreased the bin size for cfDNA fragment length analysis, the performance of the model was significantly improved even with the same number of bins. Since the model with smaller bin size performed better, we could decrease the size target regions and data size. Our results proposed that analyzing fragment size at high resolution was an effective way to use the feature for cancer detection. By designing targeted Methyl-seq panel and generating high depth sequencing data (&gt; 1000X), we could effectively integrate DNA methylation and fragmentation patterns for non-invasive cancer detection. Conclusions: In this study, we propose a novel non-invasive CRC detection method using targeted Methyl-seq data based on the integration of DNA methylation and fragmentation patterns. The adding of fragmentation features to the methylation information was effective in improving the sensitivity and specificity of CRC detection.
Fumarate hydratase-deficient renal cell carcinoma: The real-world experience at Dana-Farber Cancer Institute and Moores Cancer Center.
Authors: Renee Maria Saliby, Chris Labaki, Wanling Xie, Taylor Nonato, Andrew Lachlan Schmidt, Ziad Bakouny, Wenxin Xu, Praful Ravi, David A. Braun, Michelle S. Hirsch, Rana R. McKay, Toni K. Choueiri, Bradley Alexander McGregor
Journal: Journal of Clinical Oncology (2022)

e16522 Background: Fumarate hydratase (FH)-deficient renal cell carcinoma (RCC) is a rare and aggressive tumor with limited clinical trials dedicated to therapeutics for this disease. This retrospective study aimed to report a multi-center experience in the systemic treatment of FH-deficient RCC. Methods: The medical records of patients undergoing systemic therapy for advanced or metastatic FH-deficient RCC at Dana-Farber Cancer Institute and Moores Cancer Center were reviewed from 2012 to 2021. Demographic, histologic, molecular, and survival parameters were collected. Response was assessed using RECIST 1.1 criteria. A confirmative initial diagnosis of FH-RCC was made utilizing FH/2SC immunohistochemistry (n = 12) and/or the presence of an FH mutation (n = 6). The primary endpoint of this study was to characterize patients with FH-deficient RCC in the modern era. Results: 18 patients were included; median age at diagnosis was 45 (interquartile range [IQR]: 40-55) years. All patients had a Karnofsky Performance Status (KPS) ≥ 80. Among 14 patients with evaluable IMDC criteria, 1 (7.4%) had favorable-risk disease, while 10 (71.4%) and 3 (21.4%) had intermediate- and poor-risk disease, respectively. Tumors at diagnosis were stage III (n = 6, 33.3%), and IV (n = 12, 66.7%). Median time from diagnosis to the start of systemic therapy was 2.8 months. Six types of regimens were given as first-line therapy (Table). Fourteen patients (78%) developed disease progression on frontline therapy and received subsequent therapy; two patients, initially treated with an mTOR inhibitor and combined vascular endothelial growth factor (VEGF) inhibitor and immune checkpoint inhibitor (ICI), are off therapy and still under surveillance with no recurrence to date; one patient passed away while on frontline therapy; and one patient has limited follow-up. For a median follow-up of 22 months (IQR:6.4-49), the 18-month-overall survival estimate was 81% (95% confidence interval [CI]: 53%-94%) and median progression-free survival (PFS) was 6.7 months (95%CI: 5.0-17.0). Conclusions: This study shows considerable heterogeneity in the treatment for FH deficient-RCC, with disparate clinical outcomes. Dedicated trials and guidelines on the management of FH-deficient RCC are needed.[Table: see text]
Clinical trial and translational research for cancer immunology in Asian countries: Understanding the new frontier.
Authors: Mel Valerie Cruz Ordinario, Yuki Kojima, Kazuki Sudo, Namiko Iida, Shinichiro Okamoto, Kenichi Nakamura, Kan Yonemori, Keisuke Watanabe, Marcelo Severino Bulauitan Imasa
Journal: Journal of Clinical Oncology (2022)

e14510 Background: Among the major advances in cancer treatment is the progress in cancer immunotherapy; however, despite the strides, there is few information specific to the Asian population. It is unclear to what extent clinical trial and translational research in cancer immunology are conducted in Asian institutions. Methods: This questionnaire-based survey was conducted among researchers and healthcare professionals who are involved in cancer immunology research and therapeutics in Asia-Pacific countries. The study identified the involvement of respondents in various phases of clinical trials, and immunotherapy research. In addition, the current capabilities of the institutions to conduct translational research were surveyed. Results: We received a total of 122 responses from 20 Asia-Pacific countries. More than half (58%) of the responders are currently conducting clinical trials on cancer immunology with 25% having performed more than 10 Phase 3 trials in the last 3 years. In clinical trials and clinical practice, immune checkpoint inhibitors were performed in most countries (81.8% and 88.6%, respectively). Clinical trials and clinical practice of CAR-T and TCR-T were performed only in some countries (CAR-T; 22.7% and 15.9%, TCR-T; 2.3% and 0%, respectively). In the absence of novel therapeutics in their institution, 18% of the responders refer their patient to facilities that have ongoing clinical trials. Among the institutions that perform Hematopoietic stem cell transplant (55.1%), the most common type offered include autologous (81.3%) and allogenic (70.8%) peripheral blood stem-cell transplantation. About 51.7% of the respondents have institutions that can conduct early drug phase development studies with only 11.2% capable of utilizing their own immunotherapeutic agents. Less than half of the respondents (40.7%) belong to institutions that have conducted translational researches using patient-derived samples for the last three years. Furthermore, more than half of the respondent institutions have no personnel that is experienced to handle and/or run patient-derived fresh peripheral blood or fresh tumors. Collaboration among neighboring countries can allow send out of specimens to other institutions that have such capability, however, 56.9% of countries have regulations or restrictions in transporting lymphocytes or tumor tissues. Conclusions: Oncologists and researchers in Asia recognize the importance of cancer immunology researches for patients. There were institutional and inter-country differences particularly in the conduct of early phase clinical drug development and translational research.
Delayed versus immediate start of chemotherapy in asymptomatic patients with metastatic cancer: A systematic review and meta-analysis.
Authors: Simone Augustinus, Gajanan Thurairajah, Marc G Besselink, Hanneke W.M. Van Laarhoven, Martijn G.H. van Oijen, Tara Mackay, Johanna Wilmink
Journal: Journal of Clinical Oncology (2022)

12126 Background: The number of asymptomatic patients diagnosed with metastatic cancer is increasing. This is mostly due to increased used of imaging, especially for screening and during follow-up. Traditionally, chemotherapy is started immediately in these patients, but some argue that withholding chemotherapy until symptoms occur may be beneficial for patients, especially in terms of quality of life. However, the impact on survival and quality of life is unknown. The aim of this study is to give an overview of delayed versus immediate chemotherapy in asymptomatic patients with metastatic cancer. Methods: We systematically searched PubMed, EMBASE (Ovid), and Cochrane for studies investigating the timing of start of chemotherapy in asymptomatic patients with metastatic cancer. Primary outcome was overall survival (OS). Secondary outcomes included quality of life (QOL) and toxicity. A meta-analysis was performed on OS, including all studies that compared direct versus delayed chemotherapy. Quality of life was described using the global health status derived from the EORTC-QLQ-C30 questionnaire evaluated in the studies. Results: Four randomized controlled trials and one retrospective study with overall 919 patients were included. The studies considered colorectal cancer (n = 3), ovarian cancer (n = 1), and gastric cancer (n = 1). The median OS varied from 11.9 to 25.7 months in the immediate treatment group versus 9.0 to 27.1 months in the delayed group. A pooled analysis demonstrated no significant differences in OS between the groups (pooled HR 1.05, 95% CI 0.90-1.22, p = 0.52). Quality of life was evaluated in three studies and suggested a better QOL in the delayed treatment group. In two studies including colorectal cancer patients the global health status in the immediate treatment group was lower at all time-points compared to the delayed treatment group, with no significant differences in any of the separate domains. In the study evaluating ovarian cancer patients, among others, the time median time spent in good global health score was lower in the immediate treatment group. Toxicity was compared between the two groups in one study, and this showed no significant differences. Conclusions: This systematic review with meta-analysis on timing of start of chemotherapy in asymptomatic patients with metastatic cancer suggests that a delayed start of chemotherapy, as compared to immediate start, does not result in worse OS, while it may better preserve QOL. Future randomized trials, with specific emphasis on quality adjusted life years are needed.
Real-world outcomes in advanced renal cancer patients treated with stereotactic radiosurgery for intracranial metastases.
Authors: Abiola Fatimilehin, Hossain Mahabubabinta, Kennedy Stephen, Manon Rhys Pillai, Natalie Charnley
Journal: Journal of Clinical Oncology (2022)

e16516 Background: The proportion of metastatic renal cancer (mRC) patients with intracranial involvement is 8%, and 2% develop brain secondaries exclusively [1]. Although renal cancer is generally regarded as relatively radioresistant, studies have shown patients treated with stereotactic radiosurgery (SRS) demonstrate a local progression free survival (PFS) rate of 79-84% at 1 year and median overall survival (OS) of 9.6 – 13.9 months [2,3]. We evaluate the outcomes of patients with mRC who have received SRS to intracranial metastases at two tertiary centres in the North West of England. Methods: Patients who received SRS from January 2017 to July 2019 at Royal Preston Hospital, and from May 2016 to March 2021 at the Christie were retrospectively identified from the database of the respective hospitals. Clinical records were used to obtain demographics, therapies received and follow up data. Results: A total of 41 patients were identified. 31 patients (76%) were male and the average age at treatment was 59.6 years. 5 patients received treatment on &gt;1 occasion, but only the first episode was considered for analysis. 80.4% had a performance status of 0-1 and most patients had clear cell histology. 19 patients (46.3%) had lesions treated bilaterally. The median follow up time was 11 months. Prescribed doses ranged between 18Gy to 30Gy in 1-5 fractions. 11 patients (26.8%) progressed during the follow up period, with a median time to progression of 5 months. The longest time to progression was 17 months, in a patient who received Nivolumab following SRS. 28 patients (68.3%) died during the follow up period with a median time to death of 9.1 months. Median OS was 11 months, with 19 out of the 28 patients (67.9%) dying within the first year. The 1 year survival rate was 52.6% and 2 year survival rate was 16.2%. A range of systemic agents were used pre and post SRS including immunotherapy. 6 patients (23%) commenced immunotherapy following SRS (nivolumab +/- ipilimumab), with OS ranging from 6 – 49 months (average 25.5 months). Conclusions: We found that outcomes in this cohort of patients treated with SRS were comparable to previous findings. A subgroup who commenced Nivolumab following SRS demonstrated an average survival of over 2 years.[Table: see text]